This invention relates to a hydrophilic copolymer, or hydrogel, which is suitable for the production of ocular lens such as intraocular lens, contact lens or the like, and is particularly suitable for foldable intraocular lens (foldable IOL).
Intraocular lens (IOL) has been used to replace crystalline lens in cataract surgery. Since IOL was first used in implanting in 1949, various researches have been carried out on IOL materials. With the great evolution of operation methods and advancement of operation methods, demands on the characteristic features of IOL have also changed a lot. Recently, with the popularity of phacoemulsification techniques and the like, it is possible to open a very small incision to remove the opaque crystalline lens, and thus the demands on the characteristic features of implanted IOL have changed gradually. For example, in order to implant IOL through a small incision, the IOL should be in a folded form when implanted and returned to an expanding state in lens capsule, this is the characteristics of the so-called foldable IOL. Herein, various researches have been carried out on IOL materials. Polymethyl methacrylate (PMMA), silicone, acrylic resin and the like have been widely used as IOL materials, while silicone and acrylic acid resin can be used as foldable IOL materials. Recently, copolymers of hydroxyethyl methacrylate, methyl methacrylate and the like have also been used as foldable IOL materials. Moreover, besides the studies on these IOL materials, the following techniques have been adopted in the practical use: an ultra-violet (UV) light absorber such as hydroxybenzophenone or hydroxyphenyl benzotriazole has been added to the IOL materials to avoid the effect of UV light on retina; polysaccharide such as heparin is coated on IOL surface to improve biocompatibility and to avoid cell deposition and the like.
One characteristic of the copolymer according to the present invention is that it contains acrylic monomer having a pyrrolidone group as its structural unit. There have been reports on this kind of polymer, especially those used in ocular lens, such as copolymer of methacryloyl-oxyethyl-2-pyrrolidone and acrylic acid and the like (JP Laid-Open 28705/1992); polymer prepared from monomer which is formed from amidation of acrylic acid and pyrrolidone (JP Laid-Open 43208/1990); polymer of polyoxyalkylene skeleton having a pyrrolidone group (JP Laid-Open 8218/1990) and so on. In particular, as for copolymers prepared from three components or more, only the following several kinds have been disclosed: copolymers prepared from vinyl pyrrolidone and hydroxyethyl methacrylate or methyl methacrylate (JP Laid-Open 105250/1978); copolymer prepared from methacryloyloxyethyl-2-pyrrolidone, alkyl methacrylate and fluoroalkyl methacrylate (JP Laid-Open 150197/1993) and so on. However, these materials were studied mainly for the applications in soft contact lens and not in IOL, the possibility of application in foldable IOL as described in this invention has totally not been suggested.
It is an object of the present invention to provide a kind of ocular lens such as intraocular lens, contact lens and the like, to say in more detail, it is used mainly as foldable intraocular lens (foldable IOL). For the study of foldable IOL materials, their properties including refractive index, surface strength, tensile strength, recovering speed, transparency and the like should be considered. For example:
1) if the refractive index of IOL is too low, the thickness of IOL would increase too much, thus contraction difference of periphery would become over large. So it is necessary for IOL to have a proper refractive index. Specifically, the preferable range of refractive index is 1.4-1.6.
2) because tweezers are used to implant foldable IOL, surface strength and tensile strength of IOL bearing the operation is needed.
3) after foldable IOL is implanted, it must be returned to its original form in lens capsule. Recovering speed can be varied with the difference of habit and ability among operators. In general, the possibility of mechanical invasion of peripheral tissue increases with the increase of recovering speed. On the other hand, with the slowdown of recovering speed, the operation in turn gets longer, the possibility of bad effects on peripheral tissue also increases. Accordingly, suitable recovering speed is needed for foldable IOL.
Moreover, the material should be easily shaped into IOL. Only when the above requirements are satisfied can different kinds of foldable IOLs find practical use, and more preferable material be developed. For example, though the commercially available silicone foldable IOL has suitable refractive index, its recovering speed is too fast; when acrylic foldable IOL is implanted with tweezers, compressive mark or scar may possibly form. The operators must be very skillful when using these two IOLS. In addition, silicone foldable IOL can not resist to damage from laser, is easy to chap and pit, and has the possibility to form white turbidness.
Furthermore, to avoid the effect of UV light on retina, a more preferable material can be obtained if an UV absorber is added, so it is expected to develop a kind of excellent material with both the above mentioned properties and at the same time having the ability to absorb UV light.
The present inventors, with the consideration to solve the above problems, have investigated the more applicable foldable IOL materials, and have found that a four component copolymer prepared from acrylic derivatives having pyrrolidone groups could be used as a kind of particularly excellent IOL material.
The present invention relates to a novel copolymer prepared from the copolymerization of the following monomers a), b), c) and d), to the process for preparing the copolymer, and to the ocular lens thereof.
a) 
[wherein R1 represents hydrogen or a lower alkyl group; R2 represents a lower alkylene group, which can be replaced by a hydroxyl group, and there can be oxygen in the alkylene group chain. The followings are same.]
b) 
[wherein R3 represents hydrogen or a lower alkyl group; R4 represents the following radicals or a single bond, 
R5, R6, R7 and R8 represent hydrogen or a lower alkyl group, respectively. m, n, p and q are integers of 1 to 4. The followings are same.]
c) 
[wherein R9 represents hydrogen or a lower alkyl group; R10 represents a lower alkyl group. The followings are same.]
d) 
[wherein R11 represents hydrogen or a lower alkyl group; R12 represents a phenyl lower alkyl group, a naphthyl lower alkyl group, a pyrimidyl group, or a pyrimidyl piperazinyl group. The phenyl ring of the phenyl lower alkyl group and naphthyl ring of the naphthyl lower alkyl group can also be replaced by a lower alkyl group, a lower alkoxy group or a halogen atom. X represents xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94 or a single bond. The followings are same.]
When structural units are used to represent the copolymers, the copolymers are composed of the following four components: [I], [II], [III] and [IV], wherein the weight ratios are 40-80 for [I], 5-30 for [II], 5-20 for [III] and 5-30 for [IV], respectively. 
The preferred weight ratios of the said components in copolymers according to the present invention are 50-70 for [I], 10-25 for [II], 5-15 for [III] and 5-20 for [IV].
The said weight ratio of the component is based on the total weight of the copolymer, which is obtained by mixing and polymerizing the described weight of the respective components (monomers).
Following is the detailed description of the above-mentioned groups. The said lower alkyl group is straight or branched chain alkyl groups having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, hexyl and the like; lower alkoxy group is straight or branched chain alkoxy groups having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, hexyloxy and the like; lower alkylene group is straight or branched chain alkylene groups having 1 to 6 carbon atoms such as xe2x80x94CH2xe2x80x94, xe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)3xe2x80x94, xe2x80x94CH(CH3)2xe2x80x94, xe2x80x94(CH2)4xe2x80x94, xe2x80x94(CH2)6xe2x80x94 and the like. The halogen atom is fluorine, chlorine, bromine or the like.
The preferred examples of the above-mentioned groups are that R1 is hydrogen or methyl; R2 is xe2x80x94(CH2)2xe2x80x94 or xe2x80x94(CH2)3xe2x80x94; R3 is hydrogen or methyl; R4 is xe2x80x94OCH2xe2x80x94 or xe2x80x94OCH2CH2xe2x80x94; R9 is hydrogen or methyl; R10 is methyl, R11 is hydrogen or methyl, R12 is a benzyl, phenethyl or pyrimidyl piperazinyl group.
It is preferable to use the above-mentioned groups in combination. The particularly preferred combination is that R2 is methyl; R2 is xe2x80x94(CH2)2xe2x80x94; R3 is hydrogen; R4 is xe2x80x94OCH2CH2xe2x80x94; R9 is methyl; R10 is methyl, R11 is hydrogen or methyl, R12 is a benzyl, phenethyl or pyrimidyl piperazinyl group.
The copolymers according to the present invention can be obtained by copolymerization of monomers a), b), c) and d), polymerization initiators such as potassium persulfate, ammonium persulfate, benzophenone, methacryloyloxy benzophenone and N, N-dimethylaminoehtyl methacrylate are preferably selected singly or in combination to initiate the copolymerization. In general, azobisisobutyronitrile is widely used as a polymerization initiator in copolymer synthesis, but when it is used in the synthesis of foldable IOL materials, which is the application purpose of the present invention, physical strength of the resulted polymer is not satisfactory. The present inventors have made an extensive study on polymerization initiators and have also found that copolymers with satisfying physical strength for IOL material can be obtained by using potassium persulfate, ammonium persulfate, benzophenone, methacryloyloxy benzophenone or N, N-dimethylaminoehtyl methacrylate or a mixture thereof as polymerization initiators.
Moreover, it is preferable that the molecular weight (viscosity-average molecular weight) of the copolymer according to the present invention is ten thousand or higher. In general, molecular weight has no effect on the characteristics of a copolymer, and it is not an important factor, but it has an effect on the physical strength of a copolymer. When the molecular weight is lower than ten thousand, the relationship between the molecular weight and physical strength of a copolymer is nearly linear proportional. But if it is higher than ten thousand, physical strength of the copolymer approaches maximum and the value is almost constant. Accordingly, material with stable physical strength can not be obtained if the molecular weight is ten thousand or lower, and it is likely to be troublesome when the material is used as foldable IOL. But when the molecular weight is higher than ten thousand, there will be few problem. However, if the molecular weight is too high, foldable IOL becomes brittle, which is not anticipated. Accordingly, the preferred range of the molecular weight of the copolymer is from ten thousand to one hundred thousand. The molecular weights of the copolymers in the following examples are just within the above range.
In accordance with the constitution of the present invention, by appropriately selecting the ratio of every structural unit, the properties of the copolymer, such as surface strength, tensile strength, recovering speed, water content and the like, can be designed according to needs. The main roles of each component are as follows:
Component (I) can be obtained from a widely used monomer for polymer synthesis. The monomer is readily available at very low price. This component is an important component of the copolymer according to the present invention. However, this component itself does not play a very important role in determining copolymer properties. Increase of its ratio would increase the hydrophilicity of the copolymer, but it hardly does any effect on refractive index and recovering speed of the copolymer.
Component (II) is one characteristic component of the copolymer according to the present invention. Increase of its ratio would increase the refractive index and hydrophilicity of the copolymer.
Component (III) is also related to the copolymer properties. Increase of its ratio would increase the recovering speed and surface strength of the copolymer; but too much of (III) in the copolymer would result in the decrease of refractive index and hydrophilicity of the copolymer.
Component (IV) is one characteristic component of the copolymer according to the present invention, and increase of its ratio unit is related with the increase of refractive index.
It is possible to obtain the expected foldable IOL through preferable use of these characteristics. The preferable ratio of each component is the same as in the above description. If the preferable ratio is used, an excellent foldable IOL can be obtained. The refractive index of the IOL is 1.4-1.6, the recovering speed is neither too fast nor too slow, i.e. 3-6 seconds; and the surface strength is just the one which would fully bear tweezers operation, that is to say, the surface strength of IOL is 10 psi or higher after it is actually implanted into eyes (in swollen state).
Foldable IOL according to the present invention can fully endure tweezers operation and laser irradiation, which is free from the drawbacks of acrylic foldable IOL, such as the possibility of compressive marks or scars formation when implanted with tweezers. It also avoids the problem of pit formation when exposed to laser, which is the disadvantage of silicone foldable IOL.
Moreover, since the recovering speed can also be adjusted according to the habit of each operator as mentioned above, it can be designed to be 3-6 seconds with 2 seconds variation amplitude.
Foldable IOL can be hydrophobic and hydrophilic, and it is used depending on application purpose. But the copolymers according to the present invention are hydrophilic. Hydrophilic IOL can be circulated and stored in dry state. Before utilization, the xe2x80x9cdryxe2x80x9d IOL is wetted and swollen in purified water, and then implanted into eyes. Hydrophilic foldable IOL can also be stored in swollen state or wet state. The hydrophilicity of IOL can be deduced according to its water content, and it affects the biocompatibility, flexibility and the like of the foldable IOL. Under the conditions of the present invention, water content can be chosen by selecting the ratio of each structural unit. The preferred range of water content is 15-50%.
The copolymers according to the present invention can be subjected to inter-molecular crosslinking, and their physical strength and water content can be adjusted by crosslinking. The crosslinking agents can be acrylate or acrylamide-based compounds, for example, ethylene glycol bismethacrylate, diethylene glycol bismethacrylate or N,N-methylene bis(acrylamide) and the like. If the amount of crosslinking agent used is too large, the resulted copolymer would become hard, and its recovering speed would become fast, however, the copolymer becomes brittle. The amount of the crosslinking agent used is in the range of 0.01-2% by weight based on the total weight of the monomers (almost equal to the weight of the copolymer), and it is preferably in the range of 0.05-1.5%.
To avoid the effect of UV light on retina, currently, the widely used method is to add an UV absorber in IOL. However, in the present invention, the UV absorber can also be contained as one component of the copolymer. The UV absorbers include, for example, acrylic derivatives containing benzophenone or benzotriazole moieties, among which those with the following structures are preferable, and 4-methacryloyloxy-2-hydroxybenzophenone is particularly preferable. 
In order to improve the biocompatibility of IOL and to avoid cell deposition and the like, the technique of polysaccharide coating on IOL surface has often been used recently. Because there are free hydroxyl groups on the terminals of the copolymer chains according to the present invention, which can form covalent bonds with polysaccharides, separation of the coatings can be prevented. In addition, the covalent bond can be very readily formed, for example, only divinyl sulfone treatment can be successful. The polysaccharides include, for example, heparin or hyaluronic acid and its salts (sodium salt, potassium salt and the like).
The present invention relates to flexible and soft IOL materials. When IOL is treated with tweezers, tweezers marks would commonly be formed on the IOL surface, and it takes some time for IOL to return to its original shape. However, the copolymers according to the present invention have sufficient surface strength and excellent recovering property, thus the above problems can be solved.
Furthermore, laser can be used to cure secondary cataract and the like. But if it is conducted after IOL implantation, the former silicone IOL would chap and form turbidness, and also has the possibility to damage the transparency and to induce slight denaturalization of the neighboring portions. But when the copolymers according to the present invention are used, the possibility of the above mentioned turbidness formation is very little, transparency of the material can be maintained, in addition, it will hardly lead to any denaturalization of the neighboring portions.
The copolymer according to the present invention can be easily processed in practical shape and be used as foldable IOL. It can be shaped according to the known methods.
The copolymer according to the present invention is particularly suitable for foldable IOL, and their properties are also suitable for soft contact lens.